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The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins

Harrington LS; Findlay GM; Lamb RF et al. · 2004 · The Journal of Cell Biology · Atlas ID HAR2004

What this study shows

One half of the discovery of mTORC1's main negative feedback loop. When mTORC1/S6K1 activity is left switched on, S6K1 phosphorylates IRS-1 and represses its expression, so the insulin receptor can no longer signal to PI3K. This is the textbook explanation for why blocking mTOR paradoxically RAISES Akt activity, and a major contributor to the insulin resistance seen with chronic rapalog dosing.

Tier D because it is mechanistic or in-vitro work (model: Mammalian cells (TSC1/TSC2-null MEFs, human cells)), not a whole-organism health-outcome study; tier describes study design, not quality -- this is often exactly where causal biology gets established.

At a glance

Evidence tier	D Mechanistic / in vitro / review
Study type	5 - Mechanistic / In Vitro
Model system	Mammalian cells (TSC1/TSC2-null MEFs, human cells)
Journal	The Journal of Cell Biology
Year	2004
Peer reviewed	Yes
Record last updated	2026-07-29
Source	DOI 10.1083/jcb.200403069 · PMID 15249583

Extracted findings

Intervention	Genetic loss of TSC1/TSC2; S6K1 activity manipulation
Target	S6K1 -> IRS-1 -> PI3K/Akt
Model	Mammalian cells
Effect	Sustained S6K1 activity depletes IRS-1 and uncouples the insulin receptor from PI3K

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Abstract

Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Read the full abstract on PubMed →

Cite this record

Barton, O. (2026). The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins — evidence-graded record HAR2004. In Oliver's mTOR Atlas. https://mtor-atlas.org/study/HAR2004/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_HAR2004,
  author       = {Barton, Oliver},
  title        = {{The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins} --- evidence-graded record HAR2004},
  howpublished = {Oliver's mTOR Atlas},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/HAR2004/},
  note         = {Dataset DOI: 10.5281/zenodo.22059963}
}

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